Psychotic illnesses usually first emerge in young people and result in widespread suffering, protracted disability, premature death, and a huge economic burden. Early intervention represents a vital strategy to reduce this burden. Psychotic disorders are preceded by a prodromal period of distress, impaired functioning and subthreshold psychosis. Our original research operationally defined the Ultra or Clinical High Risk (UHR or CHR) state, which predicts a substantially increased risk of incipient psychosis. Evidence from 11 RCTs indicates that interventions can reduce the risk of transition by >50%. However, clinicians remain unclear how to select the best sequence of treatments to prevent progression and maximize recovery. This research will conduct a sequential multistage randomized clinical trial (SMART) to build individualized adaptive treatment strategies to reduce the risks for a range of outcomes. The study capitalizes on extensive Australian experience in conducting RCTs in CHR patients combined with internationally unique clinical infrastructure constructed in Australia through the headspace youth mental health model. Headspace has already delivered care to over 100,000 young people with emerging mental disorders, of whom 40% are CHR positive. From 2006, Orygen Youth Health Research Centre designed and implemented nationally this innovation in health care and directly manages 4 headspace centres treating over 5000 patients per annum. US CHR research centres do not at present have this level of access. Orygen is Australia's largest mental health research facility, and specializes in early intervention in young people. A complementary blend of US expertise in sample enrichment, clinical trial methodology and translational health services research completes this US- Australian collaboration. 500 patients will be recruited over a two year period and enter step 1 which involves a 6 week open stage of Support and Problem Solving (SPS). Non-responders (50%) will be randomized in step 2 to Aspirin + SPS, Aspirin + Cognitive-Behavioural Case Management (CBCM), Placebo + SPS or Placebo + CBCM. This is the key experimental step of the design which will study the efficacy of CBCM and aspirin, a new experimental treatment targeting inflammation as a potential mechanism. Biomarkers and cognitive vulnerability markers will be measured and their relationship to response will be studied. Step 3 (estimated n=125) will be offered to all non-responders to step 2 and will involve a randomized comparison of antidepressants and placebo with stratification for level of depression. Non-responders at 12 weeks (and drop outs) in step 3 will follow a fast fail pathway and will be offered a choice of Omege 3 fatty acids (fish oil) or low dose antipsychotic medication via a shared decision making process. Responders at each stage will be followed through a randomized design contrasting SPS and monitoring with monitoring alone. Pilot testing of the staged model naturalistically in a US CHR clinic and focus groups with various US stakeholder groups will address issues related to translation to US healthcare.